tbuckley/cabot-search huggingface dataset:
HGG-22. PROGNOSTIC FACTORS FOR PEDIATRIC, ADOLESCENT, AND YOUNG ADULT PATIENTS WITH NON-DIPG GRADE 4 GLIOMAS: A CONTEMPORARY POOLED INSTITUTIONAL EXPERIENCE
Authors: Jennifer Matsui, Pamela Allen, Haley Perlow, Jason Johnson, Arnold Paulino, Mary McAleer, Maryam Fouladi, David Grosshans, Amol Ghia, Jing Li, Wafik Zaky, Murali Chintagumpala, Joshua Palmer, Susan McGovern
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND WHO grade 4 gliomas are rare tumors in the pediatric and AYA (adolescent and young adult) population. In this study, we evaluate prognostic factors, toxicities, and outcomes in the pediatric versus AYA population. METHODS This retrospective pooled institutional study included patients &amp;lt; 30 years old with grade 4 gliomas. Overall survival (OS) and progression free survival (PFS) were characterized using Kaplan-Meier and Cox regression analysis. RESULTS Ninety-seven patients (n=20 &amp;lt; 15y, n=77 ≥ 15y) were identified with a median age 23.9y at diagnosis. Most had biopsy-proven glioblastoma (91%) and the remainder had diffuse midline glioma, H3K27M-altered (9%). All patients received surgery and adjuvant radiotherapy. Median PFS and OS were 20.9 months and 79.4 months, respectively. Gross total resection was associated with better PFS in multivariate analysis [HR 2.00 (1.01–3.62), p = 0.023]. Age ≥15y was also associated with improved OS [HR 0.36 (0.16–0.81), p = 0.014] while female gender [HR 2.12 (1.08–4.16), p = 0.03] and K27M altered histology [HR 2.79 (1.11–7.02), p = 0.029] were associated with worse OS. Only 7% of patients experienced grade 2 toxicity during radiation. Sixty-two percent of patients experienced tumor progression, 28% local and 34% distant. Analysis of salvage treatment found reirradiation was not associated with improved OS, but second surgery and systemic therapy significantly improved survival from the time of tumor progression. CONCLUSIONS Age is a significant prognostic factor in WHO grade 4 glioma, which may reflect age-related molecular alterations in the tumor. Diffuse midline glioma was associated with worse OS compared to hemispheric glioblastoma; this may be related to lack of effective targeted therapies. Surgery and systemic therapy were effective salvage options that significantly improved outcome. Better understanding of prognostic factors may guide future treatment within this understudied patient population, and prospective studies are warranted.
OUTC-05. DIFFERENCES IN FACTORS INFLUENCING SURVIVAL IN CHILDHOOD AND ADULT CNS MALIGNANCIES
Authors: Jashanjeet Matharoo, Hayden Dux, William Broaddus
Journal: Neuro-Oncology (2023)

Abstract Socioeconomic factors such as income and community type have shown to correlate with outcomes in neuro-oncologic care. In pediatric populations, however, fewer conclusions have been drawn on the effects of factors such as race, gender, and insurance status on survival due to the relative rarity of such cases. This analysis utilizes the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) program database to determine differences in factors influencing survival in both pediatric and adult CNS malignancies. From the SEER Research Nov 2020 (1975-2018) dataset, 29865 patients with malignant CNS tumors (identified by ICD-0-3 code) diagnosed between 1990-2018 and directly causing patient demise were selected and data were collected on age at diagnosis, sex, race, median household income (in 2019 USD), community type (rural-urban continuum), and survival (in months). This cohort was separated into pediatric (ages 0-19, n = 1509) and adult (ages 20 and above, n = 28356) subgroups and independent survival analysis was conducted by income, community type, sex, race, and decade of diagnosis. Kaplan-Meier curves were visualized for each comparison. Log rank analysis of survival in the pediatric cohort showed greater mortality in females (p = 0.0224) and in the most recent decade (p &amp;lt; 0.0001). The same analysis in the adult cohort showed greater mortality in lower income groups, more rural community settings, females, patients categorized as White, and in the most recent decade (p &amp;lt; 0.0001 for all comparisons). Unlike in the adult population, income, community setting, and race were not associated with significant differences in survival in the pediatric population, prompting further investigation into healthcare delivery differences between pediatric and adult populations. Further study should focus on the cause of these discrepancies to improve equity in neurosurgical care.
ATRT-12. HYPERACTIVATING THE INTEGRATED STRESS RESPONSE WITH PROTEASOME INHIBITION IN AT/RT
Authors: Orlandi Novak, Tyler Findlay, Jeffrey Rubens, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2023)

Abstract Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive pediatric brain tumor with a poor prognosis. AT/RT has increased baseline activation of the integrated stress response (ISR), an evolutionarily conserved system that enables cells to tolerate various forms of stress. Elevated expression of ATF4 indicates activation of the ISR. Transient or low-level expression of this transcription factor protects cells from stress, while sustained, high-level activation results in cell death. Ixazomib is an orally bioavailable proteasome inhibitor that causes endoplasmic reticulum stress, which is a major upstream activator of the ISR. Because AT/RT has a high baseline level of ATF4, we hypothesized that this tumor would be susceptible to ISR activators such as ixazomib. After determining the IC50 of ixazomib, AT/RT cell lines were treated with increasing concentrations of the drug. Cleaved caspase-3 immunofluorescence showed a significant increase of apoptosis (CHLA06 p&amp;lt;0.0001 by ANOVA). We are currently testing ixazomib in combination with idarubicin, a brain-penetrant anthracycline, and gemcitabine, a brain-penetrant nucleoside analog. Synergy testing in CHLA06 showed an overall zero-interaction-potency (ZIP) synergy score of 23.464 with inhibitory concentrations of ixazomib and idarubicin in the low nanomolar range (scores of 10 or above indicate synergy). Similarly, ixazomib and gemcitabine synergized to suppress CHLA06 growth and induce apoptosis (67% Annexin V+ cells in combination compared to 14 and 24% Annexin V+ with single agent treatment). In the future, we will determine if ixazomib selectively kills AT/RT while sparing normal cells in iPSC brain organoids. We will also test ixazomib in orthotopic xenografts of AT/RT. These results suggest that ixazomib, especially in combination with idarubicin, gemcitabine or other ISR activators, has the potential to serve as an effective therapy for AT/RT.
BIOL-03. NOVEL GENETICALLY ENGINEERED MOUSE MODEL FOR CHOROID PLEXUS CARCINOMA MIMICS HUMAN DISEASE
Authors: Matilde de Almeida Duarte, Richard Gilbertson, Jessica Taylor, Amir Jassim, Linda Hu
Journal: Neuro-Oncology (2023)

Abstract Choroid plexus carcinomas (CPCs) are rare, aggressive malignant tumours of the central nervous system occurring mainly in children under the age of one. While advances in clinical and molecular stratification have enabled risk-adapted treatment planning and improvements in outcome for many types of childhood brain tumours, there has not been equivalent progress for children with CPC. This has largely been due to the low incidence, leading treatment strategies to be mostly based on case series and a “standard of care” has yet to be established. In order to elucidate a coordinated therapeutic strategy for children with CPC, it is imperative to develop in vitro and in vivo models to improve our understanding of the mechanisms underlying tumorigenesis. We hypothesised that we could develop a genetically engineered mouse model (GEMM) to recapitulate patient CPCs, allowing for an early age of onset and high penetrance rate for accurate and efficient preclinical studies. To develop this GEMM of CPC, we utilized Cre-Lox technology to target CPC cells of origin. We crossed mice that conditionally expressed Tp53 flx/flx; Rb flx/flx; Pten flx/flx with mice harbouring a Tg(Ttr-cre/Esr1*)1Vco allele, as it drives selective Cre-recombination in the early embryonic choroid plexus. Using this methodology, we have managed to produce CPCs within 90 days and with a 95% penetrance rate which we characterised using our laboratory’s tumour characterisation pipeline comprising histological evaluation, transcriptome analysis and imaging. We then used this model to investigate the transformation of the choroid during tumorigenesis and test novel therapeutic approaches to improve outcomes for patients affected by CPC. Not only are we looking for a “standard of care” that is currently inexistent for CPC, but we are also looking for one that will have minimal side effects and, therefore, not jeopardise the future of these children.
TRLS-05. PRELIMINARY RESULTS FROM A PHASE I TRIAL TO EVALUATE INTRAVENTRICULAR DELIVERY OF IL13RΑ2-TARGETING CAR T CELLS AFTER LYMPHODEPLETION IN PEDIATRIC BRAIN TUMORS PATIENTS
Authors: Tom Davidson, Angela Oill, Melody Wu, Colt Egelston, Heini Natri, Sean Sepulveda, Jonathan Hibbard, Jamie Wagner, Monica Nisis, Julie Kilpatrick, Tracey Stiller, Joseph Georges, Margarita Munoz, Cheryl Oliver-Cervantes, Jennifer Shepphird, Julie Ressler, Massimo D’Apuzzo, Maryam Aftabizadeh, M Suzette Blanchard, Behnam Badie, Christine Brown, Nicholas Banovich, Leo Wang
Journal: Neuro-Oncology (2023)

Abstract Brain tumors are the leading cause of cancer death in children, and outcomes for patients with recurrent or aggressive disease remain poor. We have previously shown that locoregionally-delivered chimeric antigen receptor (CAR) T cells targeting the high-affinity IL13 receptor IL13Rα2 are safe and well-tolerated in adults, and that they can mediate a remarkable clinical response. This antigen is also expressed on roughly half of pediatric neuromalignancies. Here, we present the clinical experience from the first patients treated with IL13BBζ-CAR T cells on our trial. Patients received four doses of CAR T cells, delivered weekly through an indwelling CNS catheter; the first dose was 1e7 CAR T cells and subsequent doses were 5e7 cells. The first three patients received CAR T cells alone; the rest received lymphodepletion with cyclophosphamide and fludarabine before CAR T cell infusion. After follow-up imaging at the end of the dose-limiting toxicity (DLT) period, patients were given the option to continue therapy. Six patients have been treated without DLTs; one patient on the lymphodepletion arm did not complete the four infusions due to a Grade 3 catheter-related infection. Other patients experienced occasional Grade 3 AEs that were not attributed to CAR T therapy, with the exception of headache, muscle weakness, and ALT elevation. Otherwise, AEs were Grade 1-2. Five patients completed four infusions and were evaluable at the end of the DLT period. Of those, three experienced radiographic and/or clinical benefit, although none met protocol criteria for a partial response. Specific cytokines were increased in the cerebrospinal fluid (CSF) of patients during radiographic response periods. Additionally, single-cell transcriptomic analysis paired with TCR sequencing of CSF cells demonstrated characteristic immune signatures correlated with response. These preliminary results support combining lymphodepletion and repeated intraventricular CAR T cell delivery as a promising therapy in children with brain tumors.
MDB-26. CDK8 IS AN ONCOGENE IN GROUP 3 MEDULLOBLASTOMA THAT IMPACTS PROTEIN TRANSLATION BY REGULATING THE TRANSCRIPTIONAL ACTIVITY OF RIBOSOMAL GENES
Authors: Dong Wang, Bethany Veo, Angela Pierce, Caitlin Ritz, Rajeev Vibhakar
Journal: Neuro-Oncology (2023)

Abstract Medulloblastoma (MB) is one of the most common malignant childhood brain tumors. Single-cell RNA-seq analysis of human medulloblastoma patients revealed that Group 3 MBs are dominated by undifferentiated progenitor-like cells with elevated expression of ribosomal genes, suggesting that overactive ribosome biogenesis is a hallmark of Group 3 MB. Using CRISPR-Cas9 screen, we found that Cyclin-dependent kinase 8 (CDK8) is an essential gene for MYC MB viability. We showed that CDK8 facilitates MYC-driven transcriptional programs and is necessary for sustaining expression of MYC. Furthermore, the loss of CDK8 resulted in a reduction in the phosphorylation of RNA polymerase II CTD and caused significant changes in genome transcription. Using cut&amp;run, we found CDK8 directly regulated ribosomal gene transcription activity. CDK8 inhibition impaired ribosome biosynthesis suppressed protein translation and led to a striking reduction in phospho-Pol II binding at the promoter regions and gene bodies of SE-associated genes. The combination of an mTOR inhibitor with CDK8 inhibitors showed remarkable synergy in suppressing ribosome biogenesis, decreasing cell viability and attenuating tumor growth in vitro and in multiple models of MB. This proposal outlines the mechanistic consequences of CDK8 inhibition on ribosome biogenesis and provides pre-clinical validation of CDK8 inhibitor treatment as a novel therapeutic approach in MYC MB.
DIPG-03. IDENTIFICATION OF NEW THERAPEUTIC TARGETS BY ARRAYED CRISPRA-BASED APPROACH TO MAP RADIORESISTANCE IN DMG
Authors: Solène Fernandez, Sandra Laternser, Stefano Sellitto, Sandesh Neupane, Antonela Petrovic, Ludovica Ciani, Bettina Kritzer, Kerstin Hasler, David Bamert, Javad Nazarian, Adriano Aguzzi
Journal: Neuro-Oncology (2023)

Abstract Pediatric Diffuse Midline Glioma (DMG) is amongst the most aggressive childhood brain tumors. The dismal prognosis is less than a year for children diagnosed. Radiotherapy (RT) remains the only standard treatment that provides only transient relief of clinical symptoms of DMG patients. Poor survival is associated with radio-resistance due in part to P53 mutational status and to invasive tumor properties related to epigenetic dysregulation. Over 80% of DMG patients harbor oncohistone 3 mutations (H3K27M) leading to global genome hypomethylation and transcriptional disruption. Transcriptional factors are known as master regulators of the genome but their implication in response to radiation treatment remains unclear. We developed an arrayed-CRISPR screen strategy to understand the role of transcription factors in radioresistance mechanisms in DMG-patient-derived cells. We performed arrayed-CRISPRa screening in multiwell plates with DMG cells expressing the dCas9-VP64, infected with gRNA lentiviral library to target each transcription factor (one transcription factor overexpressed per well). Each plate was irradiated fractionally (2Gy/day) and after irradiation stopped a comparison between cells overexpressing one targeted transcription to internal controls (non-targeted-gRNA infected cells) has been conducted. Transcription factor “hits” identification is based on Log2FC (logarithm 2 fold-change) with a value higher than 0.6, considering these targets as potentially involved in DMG cell radio-resistance and/or proliferation mechanisms. We identified 82 “hits” with more than 30% described as involved in radio-resistance mechanisms and/or tumorigenesis process, sustaining our screen results. We focus on “hits” with a Log2FC higher than 1 to identify the most robust targets playing a role in resistance to radiation. Currently, DMG cells are being treated with RT combination with pharmacological inhibitors to validate our candidate target involvement in DMG radio-resistance. Our goal is to achieve a better understanding of resistance mechanisms to identify therapeutic treatments to combine with radiotherapy to overcome radio-resistance developed by DMG cells.
DIPG-55. DIRECT BRAIN-TO-BRAIN WORKFLOW ENABLES THE PRECLINICAL MODELING OF PEDIATRIC GLIOMAS
Authors: Hong Tum, Christopher Tse, Jennifer Salinas, Nicholas Bayley, Henan Zhu, Timothy Cloughesy, Linda Liau, Thomas Graeber, David Nathanson
Journal: Neuro-Oncology (2023)

Abstract Pediatric high-grade gliomas (pHGG) are one of the leading causes of brain cancer deaths in children. Progress towards the characterization of molecular and genetic features in adult high-grade gliomas and subsequent therapies has not yielded similar results in pHGG patients. pHGGs do not readily establish in culture and there has also been a lack of preclinical models to identify new therapeutic targets. Here, we employ a direct brain-to-brain workflow enabling the establishment of rare pediatric tumors including Atypical Teratoid/Rhabdoid Tumor (ATRT), H3_K27ALT diffuse midline gliomas, and H3_G34MUT diffuse hemispheric xenograft models. These Direct, Patient-Derived Orthotopic Xenografts (DPDOX) models recapitulate the clinical, genomic, and transcriptomic landscape of that of the parental tumors. Moreover, we have incorporated each tumor with a secreted gaussia luciferase reporter enabling the minimally-invasive tracking of intracranial tumor burden over time in response to drug perturbations. Taken together, we present a novel approach to establish pHGG models and evaluate new therapeutics.
BIOL-05. IDENTIFICATION AND VALIDATION OF PA2G4 AS A POTENTIAL THERAPEUTIC TARGET IN PEDIATRIC DIFFUSE GLIOMAS
Authors: Zaid Sirhan, Blake E Sells, Jessica Fleming, Heather R Manring, Richard T Graham, Joseph P McElroy, Saikh J Haque, Daniel R Boué, Aline P Becker, Erica H Bell, Jonathan Finlay, Arnab Chakravarti
Journal: Neuro-Oncology (2023)

Abstract Brain tumors are the second most common pediatric malignancy after leukemia. High grade gliomas have a significantly high morbidity and mortality in children, with a 5-year survival rate under 20%. This study aims to identify important biological mechanisms and proteins as prognostic biomarkers and novel therapeutic targets. We hypothesize that higher grade pediatric diffuse gliomas can be effectively targeted by knocking down expression of the proliferation associated protein 2G4 (PA2G4) that binds to MYCN and prevents its ubiquitination. LC-MS/MS proteomic profiling was performed on 28 formalin-fixed paraffin embedded primary diffuse glioma samples from Nationwide Children’s Hospital (Columbus, OH). Cox proportional hazard models were used to correlate individual proteins with progression-free survival (PFS) and overall survival (OS). Differences in fold change were calculated for each protein between low grade (LGG, grade 2) and high-grade glioma (HGG, grades 3-4) patients. Ingenuity Pathway Analysis was performed considering only proteins with p-values &amp;lt;0.05. In vitro studies were performed to evaluate the roles of PA2G4 in the SF188 glioma cell line. In comparing high- and low-grade tumors, 471 proteins were found to be significantly differentially expressed. Eighty-six and 121 proteins were significantly associated with OS and PFS, respectively. PA2G4 was expressed 2.0-fold higher in HGG vs LGG (p=0.015). Additionally, high expression of PA2G4 protein was associated with significantly worse PFS (p=0.041) and OS (p=0.035) and selected for further studies. Preliminary in vitro results showed that knocking-down PA2G4 decreased AKT phosphorylation/activation and levels of MYCN protein. Given that activated MYCN plays critical oncogenic roles in patients with poor survival PA2G4 may serve as a novel therapeutic target in higher grade pediatric diffuse gliomas. Studies are underway to unfold how PA2G4 affects treatment resistance and tumor recurrence in pediatric patients.
OUTC-03. IMPACT OF TREATMENT EXPOSURES AND SOCIOECONOMIC STATUS ON NEUROCOGNITIVE PERFORMANCE IN CHILDREN WITH BRAIN TUMORS
Authors: Leslie Chang, Palak Patel, Rachel Peterson, Sahaja Acharya
Journal: Neuro-Oncology (2023)

Abstract PURPOSE To investigate the impact of treatment exposures and socioeconomic status on neurocognitive performance in children with brain tumors. METHODS Eligible patients included those diagnosed with a brain tumor at &amp;lt;22 years of age with ≥ 1 neurocognitive assessment. Neurocognitive impairment was defined as performance 1.5 standard deviations below the normative mean using age standardized measures of intellectual function. Neurocognitive outcomes included Wechsler indices of full-scale intelligent quotient (IQ), working memory (WM), and processing speed (PS). Neurocognitive decline was defined as a negative slope. Logistic regression identified variables associated with neurocognitive impairment. Longitudinal data was analyzed using linear mixed models. RESULTS Eligible patients (n=152) had a mean neurocognitive follow-up of 50.2 months and median age at diagnosis of 9.6 years. PS was most frequently impaired in patients (37.5%) followed by IQ (20.6%) and WM (16.5%). Patients with public insurance had eight-fold increased odds of impaired IQ compared to those with private insurance (Odds Ratio [OR]: 7.59, p&amp;lt;0.001). Patients treated with CSI had eight-fold increased odds of impaired IQ (OR: 7.86, p=0.003) and almost six-fold increased odds of impaired WM (OR: 5.66, p=0.028) compared to those treated without RT. After accounting for age, change in IQ was associated with chemotherapy use (slope: -0.45 points/year with chemotherapy vs. 0.71 points/year without chemotherapy, p=0.012). Patients treated with both chemotherapy and RT demonstrated the greatest decline whereas those treated without either demonstrated no decline in any of the neurocognitive measures. CONCLUSION After treatment for pediatric brain tumors, public insurance, an indicator of low socioeconomic status, was associated with impairment in IQ with a large effect size similar to that of CSI. Chemotherapy was associated with decline in IQ with a small effect size. Combined chemotherapy and RT had additive effects on neurocognitive decline in IQ, WM, and PS.
TRLS-01. FDA ANALYSIS OF EXPANDED ACCESS USE IN PEDIATRIC PATIENTS WITH CNS TUMORS FROM 2015 TO 2020
Authors: Elizabeth Duke, Natasha Kormanik, Amy Barone, Mitchell Chan, Ramya Antony, Nicole Drezner, Paul Kluetz, Tamy Kim, Harpreet Singh, Richard Pazdur, Martha Donoghue
Journal: Neuro-Oncology (2023)

Abstract Few therapies are approved for children with central nervous system (CNS) tumors, and their prognosis is often poor. Expanded Access (EA) is a regulatory mechanism enabling patients with life-threatening or serious diseases to receive treatment with investigational drugs outside of clinical trials when no comparable or satisfactory options are available. FDA’s central database was queried for single-patient investigational new drug (spIND) applications submitted to the Office of Oncologic Diseases between January 2015-December 2020. Data collection included IND date/type/status, drug name, patient demographics. Duplicate/exempt INDs, those cancelled by physician-sponsor before initiating therapy, and those for indications occurring almost exclusively in adults or missing patient age were excluded. Of 2,901 unique spINDs granted, 534 (18%) were for patients &amp;lt;18 years old; of those, 229 (43%) were for patients with nervous system tumors. Demographics included: 53% male, median age 5.0 years (range 0.3-17); race/ethnicity reported in &amp;lt;1%. Patients were treated in 78 zip codes across 33 states; one-third of submissions were from 5 large academic hospitals. Tumor types included low-grade glioma (71), plexiform neurofibroma (35), high-grade glioma (32), DIPG/DMG (30), ATRT (27), medulloblastoma (11), ependymoma (11), other CNS tumors (12). Thirty-eight unique drugs were requested (1 to 56 spINDs per drug); 60% for kinase inhibitors, 30% for other small molecule inhibitors, and the remainder for immunotherapies/other drug types. Median time for FDA to review and deem safe to proceed was 1 day. While pediatric CNS tumors are rare, these patients made up almost half of spINDs granted for pediatric patients. Ongoing efforts are needed to assess the impact of EA on patient outcomes and ensure availability to patients, families, and institutions more widely. These data highlight interest within the pediatric neuro-oncology community in accessing innovative therapies, which supports early investigation of promising new drugs for these patients.